Increasing the accumulation of aptamer AS1411 and verapamil conjugated silver nanoparticles in tumor cells to enhance the radiosensitivity of glioma

Abstract

Radioresistance significantly decreases the efficacy of radiotherapy, which can ultimately lead to tumor recurrence and metastasis. As a novel type of nano-radiosensitizer, silver nanoparticles (AgNPs) have shown promising radiosensitizing properties in the radiotherapy of glioma, but their ability to efficiently enter and accumulate in tumor cells needs to be improved. In the current study, AS1411 and verapamil (VRP) conjugated bovine serum albumin (BSA) coated AgNPs (AgNPs@BSA-AS-VRP) were synthesized and characterized. Dark-field imaging and inductively coupled plasma mass spectrometry were applied to investigate the accumulation of AgNPs@BSA-AS and AgNPs@BSA-AS-VRP mixed in different ratios in U251 glioma cells. To assess the influences of 19:1 mixed AgNPs@BSA-AS and AgNPs@BSA-AS-VRP on the P-glycoprotein (P-gp) efflux activity, rhodamine 123 accumulation assay was carried out. Colony formation assay and tumor-bearing nude mice model were employed to examine the radiosensitizing potential of 19:1 mixed AgNPs@BSA-AS and AgNPs@BSA-AS-VRP. Thioredoxin Reductase (TrxR) Assay Kit was used to detect the TrxR activity in cells treated with different functionally modified AgNPs. Characterization results revealed that AgNPs@BSA-AS-VRP were successfully constructed. When AgNPs@BSA-AS and AgNPs@BSA-AS-VRP were mixed in a ratio of 19:1, the amount of intracellular nanoparticles increased greatly through AS1411-mediated active targeting and inhibition of P-gp activity. In vitro and in vivo experiments clearly showed that the radiosensitization efficacy of 19:1 mixed AgNPs@BSA-AS and AgNPs@BSA-AS-VRP was much stronger than that of AgNPs@BSA and AgNPs@BSA-AS. It was also found that 19:1 mixed AgNPs@BSA-AS and AgNPs@BSA-AS-VRP significantly inhibited intracellular TrxR activity. These results indicate that 19:1 mixed AgNPs@BSA-AS and AgNPs@BSA-AS-VRP can effectively accumulate in tumor cells and have great potential as high-efficiency nano-radiosensitizers in the radiotherapy of glioma.

Research progress on nano-sensitizers for enhancing the effects of radiotherapy

“…Results also showed that AsNPs had better radiation sensitization than AgNPs and PEGylated AgNPs (PNPs) and induced a higher apoptosis rate. Meanwhile, Zhao et al 35 also designed AgNPs coated with AS1411, verapamil (VRP) and bovine serum albumin (BSA) (AgNPs@BSA-AS-VRP). The results showed that the mixture of AgNPs@BSA-AS and AgNPs@BSA-AS-VRP (19 : 1) could significantly accumulate in tumor cells, and the corresponding SER value was 1.55, which significantly improved the therapeutic effect of radiotherapy.…”

Multifunctional high-Znanoradiosensitizers for multimodal synergistic cancer therapy

“…34 Similar to Au nanoparticles, noble metal nanomaterials with other high-Z elements (e.g., Pt and Ir) have been developed to enhance the efficacy of RT. [35][36][37] For example, Muhammad et al found that HeLa cells treated with dendritic Pt nanomaterials showed a sharp decline in their survival curve when compared with the control group under X-ray irradiation. 38 In addition to the most commonly used high-energy X-rays, some other radioactive sources are also used in tumor RT, such as protons and neutrons.…”

Matrices and Affinity Ligands for Antibody Purification and Corresponding Applications in Radiotherapy

“…For example, As1411 is a guanine-rich DNA aptamer with high specificity and affinity to nucleolin receptors which are only overexpressed on the plasma membrane of cancer cells. The specific interaction between As1411 and nucleolin has been used to mediate the highly specific targeting of radiosensitizers to cancer cells [ 126 , 127 , 128 , 129 ]. As1411-conjugated gold nanoparticles [ 128 ], gold nanoclusters [ 126 ], or silver nanoparticles [ 127 , 129 ] have been proved to be capable of acting as efficient radiosensitizers for cancer targeting treatment.…”